Systems for perivascular nerve denervation

ABSTRACT

Provided is a catheter including a shaft having a distal end and a loop disposed near the distal end and configured to curl around a tissue and receive, via the shaft, energy for nerve denervation at least a portion of the tissue. The loop includes a body capable of bending to curl around the tissue an electrode disposed on the body and a substrate embedded in the body and separated from the electrode. The nerve denervation is performed at a loop temperature of 48° C. to 65° C. for 70 to 150 seconds.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. patent Ser. No.17/113,935 filed on Dec. 7, 2020, which is a continuation-in-part ofU.S. patent Ser. No. 16/239,718 filed on Jan. 4, 2019, which is acontinuation-in-part of U.S. patent Ser. No. 15/258,167 filed on Sep. 7,2016, all which are incorporated herein by reference in their entirety.

STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINTINVENTOR

Applicant designates the following article as a grace period publicationin order to expedite examination of the application in accordance with37 CFR 1.77(b)(6) and MPEP 608.01(a): “Laparoscopic Renal DenervationSystem for Treating Resistant Hypertension: Overcoming Limitations ofCatheter-based Approaches” published in IEEE Transactions on BiomedicalEngineering on Apr. 20, 2020 (early access). The disclosures of thearticle are incorporated herein by reference in their entirety for allpurposes.

FIELD OF THE INVENTION

The present disclosure relates to perivascular nerve 10 denervation inan autonomic nerve system, and more particularly to catheter apparatusfor perivascular nerve denervation to reduce a nerve activity.

BACKGROUND

High blood pressure is often difficult to control. Resistanthypertension is defined as a blood pressure that remains above goaldespite the concomitant use of full doses of three or moreantihypertensive drugs from different classes. One approach to treatpatients with resistant hypertension is renal denervation for blockingsympathetic nerve around the renal artery of the patients.

Recently, it has been reported that renal denervation for blockingsympathetic nerve around the renal artery using percutaneous cathetercan be effective for lowering blood pressure in patients with resistanthypertension. Besides, this renal denervation strategy has gainedattention for the usefulness in the treatment of patients witharrhythmia and cardiac failure.

However, in the existing approaches for performing renal denervation, itis difficult to destruct effectively renal nerves since most of therenal nerves are distributed far away from the intima of renal arteryand the conventional percutaneous catheters are designed to destruct therenal nerves from inner side of the renal artery. Also, the conventionalpercutaneous catheters may severely damage the intima of the renalartery as well as the adventitia of the renal artery and, in some cases,may cause angiostenosis.

Therefore, there is a need for new catheters that can help thephysicians effectively destruct the renal nerves for performing renaldenervation without damaging the renal artery and nearby organs/tissues.

SUMMARY OF THE INVENTION

The present disclosure provides a catheter apparatus for perivascularnerve denervation that effectively and completely destruct acircumferential tissue of vascular (e.g., artery), such as renal arterynerves, hepatic artery nerves, splenic artery nerves and pulmonaryartery nerves.

In accordance with one example embodiment of the present disclosure, thecatheter apparatus for perivascular nerve denervation includes: a shafthaving a distal end; and a loop disposed near the distal end andconfigured to curl around a tissue and receive, via the shaft, energyfor nerve denervation at least a portion of the tissue, wherein the loopincludes: a body capable of bending to curl around the tissue; anelectrode disposed on the body; and a substrate embedded in the body andseparated from the electrode. The nerve denervation is performed at aloop temperature of 48° C. to 65° C. for 70 to 150 seconds.

In an example embodiment of the present disclosure, the nervedenervation is performed at the loop temperature of 48° C. to 50° C. for120 to 150 seconds.

In an example embodiment of the present disclosure, the nervedenervation is performed at the loop temperature of 60° C. to 65° C. for70 to 120 seconds.

In an example embodiment of the present disclosure, the tissue is anartery including a lumen, a tunica media and a tunica adventitia.

In an example embodiment of the present disclosure, a thermal lesionboundary between the tunica media and the tunica adventitia is 1.3 mm to1.5 mm.

In an example embodiment of the present disclosure, the lumen has adiameter of 2 mm, a tunica media has a thickness of 0.5 mm and a tunicaadventitia has a thickness of 1 mm.

In an example embodiment of the present disclosure, a thermal lesionboundary between the tunica media and the tunica adventitia is 1.1 mm to1.3 mm.

In an example embodiment of the present disclosure, the lumen has adiameter of 1.4 mm, a tunica media has a thickness of 0.6 mm and atunica adventitia has a thickness of 1.2 mm.

In accordance with another example embodiment of the present disclosure,a catheter apparatus for perivascular nerve denervation, includes: ashaft having a distal end; and a loop disposed near the distal end andconfigured to curl around a tissue and receive, via the shaft, energy todenervate at least a portion of the tissue, wherein the loop includes: afirst film capable of bending to curl around the tissue; a plurality ofelectrodes disposed on the first film and arranged in parallel to eachother with a predetermined distance; and a sensor disposed at a positioncorresponding to a position between the plurality of electrodes. Thenerve denervation is performed at a loop temperature of 48° C. to 65° C.for 70 to 150 seconds.

In accordance with yet another example embodiment of the presentdisclosure, a method for perivascular nerve denervation using a catheterhaving a loop, includes: positioning the loop near a tissue, the loopincluding an electrode and a substrate; delivering energy to at leastone of the electrode and the substrate, thereby to cause the loop tocurl around the tissue; causing the at least one of the electrode andthe substrate to convert the energy into heat energy; and denervating atleast a portion of the tissue using the heat energy at a looptemperature of 48° C. to 65° C. for 70 to 150 seconds.

In an example embodiment of the present disclosure, the denervatingincludes denervating at least a portion of the tissue using the heatenergy at a loop temperature of 48° C. to 50° C. for 120 to 150 seconds.

BRIEF DESCRIPTION OF THE DRAWINGS

The objects, features and advantages of the present disclosure will bemore apparent from the following detailed description in conjunctionwith the accompanying drawings, in which:

FIG. 1 illustrates anatomy of a human kidney.

FIG. 2A is a schematic diagram of human renal nerves and renal artery.

FIG. 2B is a cross sectional view of human renal artery and renalnerves.

FIG. 3 is a schematic block diagram of a catheter system for renaldenervation according to embodiments of the present invention.

FIG. 4 is a side elevational view of a catheter according to embodimentsof the present invention.

FIG. 5 illustrates an exemplary operation of a catheter according toembodiments of the present invention.

FIG. 6A to 6D and FIG. 7A to 7D illustrate loops of the catheter in FIG.4 according to embodiments of the present invention.

FIG. 8 is a schematic diagram of a catheter, illustrating renaldenervation using the catheter according to embodiments of the presentinvention.

FIG. 9 is a flow chart illustrating exemplary steps that may be carriedout to denervate renal nerves according to embodiments of the presentinvention.

FIG. 10 is a perspective view of a distal end portion of the catheter inFIG. 4 according to embodiments of the present invention.

FIG. 11A and FIG. 11B show the loop in FIG. 10 at two differenttemperatures according to embodiments of the present invention.

FIG. 12 shows a deformation of the substrate in response to atemperature change according to embodiments of the present invention.

FIG. 13 illustrate a loop of the catheter in FIG. 4 according toembodiments of the present invention.

FIG. 14A and FIG. 14B show thermal distribution in the cross section ofthe loop a finite element modeling and FIG. 14C shows a scatter plot oftemperature normalized by a sensor showing the difference between asimulation and experimental results.

FIG. 15A shows thermal distribution at the cross section of 3D arterymodel and FIG. 15B shows thermal distribution at the longitudinalsection of the 3D artery model.

FIG. 16 shows two-dimensional temperature profiles.

FIG. 17A to 17F show heat distributions in arteries with differentsizes.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Exemplary embodiments of the present disclosure are described withreference to the accompanying drawings in detail. The same referencenumbers are used throughout the drawings to refer to the same or likeparts. Detailed descriptions of well-known functions and structuresincorporated herein may be omitted to avoid obscuring the subject matterof the present disclosure.

Components, or nodes, shown in diagrams are illustrative of exemplaryembodiments of the invention and are meant to avoid obscuring theinvention. It shall also be understood that throughout this discussionthat components may be described as separate functional units, which maycomprise sub-units, but those skilled in the art will recognize thatvarious components, or portions thereof, may be divided into separatecomponents or may be integrated together, including integrated within asingle system or component.

Reference in the specification to “one embodiment,” “preferredembodiment,” “an embodiment,” or “embodiments” means that a particularfeature, structure, characteristic, or function described in connectionwith the embodiment is included in at least one embodiment of theinvention and may be in more than one embodiment. The appearances of thephrases “in one embodiment,” “in an embodiment,” or “in embodiments” invarious places in the specification are not necessarily all referring tothe same embodiment or embodiments.

The terms and words used in the following description and claims are notlimited to the bibliographical meanings, but, are merely used by theinventor to enable a clear and consistent understanding of the presentdisclosure.

In the present disclosure, the terms such as “include” and/or “have” maybe construed to denote a certain characteristic, number, step,operation, constituent element, component or a combination thereof, butmay not be construed to exclude the existence of or a possibility ofaddition of one or more other characteristics, numbers, steps,operations, constituent elements, components or combinations thereof.

Several embodiments of the present disclosure described herein relategenerally to apparatus, systems and methods for therapeuticallyeffecting neuromodulation (e.g., nerve disruption, nerve denervation,nerve stimulation) of target nerve to treat various medical conditions,disorders and diseases. In embodiments, neuromodulation of the targetnerve may be used to treat or reduce the risk of occurrence of symptomsassociated with a variety of metabolic diseases. For example,neuromodulation of the target nerve may treat or reduce the risk ofoccurrence of symptoms associated with hypertension or otherhypertension-related diseases, diabetes or other diabetes-relateddisease. If human patient has a vascular diseases, such as hypertension,the methods described herein may advantageously treat hypertensionwithout taking hypertension drugs and if human patient has diabetesmellitus, the methods described herein may advantageously treat diabeteswithout requiring daily insulin injection or constant monitoring ofblood glucose levels. The treatment provided by the apparatus, systemsand methods described herein may be permanent or at leastsemi-permanent, thereby reducing the need for continued or periodictreatment.

In embodiments, neuromodulation of the target nerve as described hereinmay be used for the treatment of insulin resistance, genetic metabolicsyndromes, ventricular tachycardia, atrial fibrillation or flutter,arrhythmia, inflammatory diseases, hypertension, obesity, hyperglycemia,hyperlipidemia, eating disorders, and/or endocrine diseases.

The neuromodulation of the target nerve is not limited to the diseasetreatment described above and can be used to treat other suitable typesof diseases that one skilled in the art appreciates or recognizes.

FIG. 1 illustrates a common human renal anatomy. As depicted, thekidneys K are supplied with oxygenated blood by renal arteries RA, whichare connected to the heart by the abdominal aorta AA. Deoxygenated bloodflows from the kidneys to the heart via renal veins RV and the inferiorvena cava IVC.

FIG. 2A illustrates a portion of human renal artery

RA and renal nerves RN. FIG. 2B illustrates a cross-sectional view takenalong the radial plane A-A of FIG. 2A.

As depicted, the renal artery RA has a lumen through which the blood Bflows. The renal nerves RN are located in proximity to the adventitia ofthe renal artery ARA and run along the renal artery RA in a lengthwisedirection L. More specifically, renal nerves RN are situated in acircumferential tissue 5 surrounding the outer wall of the renal arteryRA and the circumferential tissue 5 may include other tissue, such aslymphatics and capillaries.

In the conventional approaches based on applying denervation energy todestroy the renal nerves RN, a catheter is inserted into the lumen anddelivers heat energy to denervate the target renal nerves RN. Duringthis process, the denervation energy may damage the adventitia ARA ofrenal artery RA before it reaches the renal nerves RN. Furthermore, aportion of the denervation energy may be absorbed by the adventitia ofthe renal artery ARA, reducing the efficiency in utilizing the energy.Accordingly, it may be more effective and safer to denervate fromoutside of the renal artery RA (i.e., apply energy from outside of RA)than to denervate from inside of the renal artery RA (i.e., apply energyfrom inside of RA).

FIG. 3 is a schematic block diagram of a catheter system 300 for renaldenervation according to embodiments of the present invention. Asdepicted, the catheter system 300 includes: a catheter apparatus 100having a distal portion 11 which may make a contact with a target tissueand/or be disposed in proximity to the target tissue for treatment; acontrol unit 200 for controlling one or more components of the system300; an energy source generator (ESG) 205 for supplying energy to thetarget tissue through the distal portion 11 of the catheter apparatus100; an imaging system 207 for processing visual images and displayingthe images to the users; and wires/cables/buses 204 that connect thecomponents of the system 300 to each other for communication. In thepresent disclosure, the target tissue is described as the renal arterynerves, but it should be apparent to those of ordinary skill in the artthat the target tissue means various artery nerves, such as renal arterynerves, hepatic artery nerves, splenic artery nerves and pulmonaryartery nerves

The control unit 200 may collectively refer to one or more componentsfor controlling various components of the catheter system 300. Inembodiments, the control unit 200 may include a digital signal processor(DSP) 201, such as CPU, and a memory 203. The memory 203 may storevarious data and include, but are not limited to: magnetic media such ashard disks, floppy disks, and magnetic tape; optical media such asCD-ROMs and holographic devices; magneto-optical media; and hardwaredevices that are specially configured to store or to store and executeprogram code, such as application specific integrated circuits (ASICs),programmable logic devices (PLDs), flash memory devices, and ROM and RAMdevices.

In embodiments, a data logger 224 may be included in the memory 203 andstore data (e.g., temperature of the target tissue) measured by thecatheter 100 during the denervation procedure. It is note that thememory 203 may be located outside the control unit 200 and coupled tothe control unit 200 via a wire/cable 204.

It is noted that the control unit 200 may be a computer, a server, orany other suitable computing facility and include other components, suchas printer, input device (such as keyboard and mouse), scanner, displaydevice, and a network interface.

In embodiments, the distal portion 11 may include denervation element(s)and optionally an endoscope or some other type of imaging device,coupled to an imaging system 207, to provide images of the target tissueusing suitable imaging techniques. The imaging device may allow theoperator/physician to visually identify the region beingablated/denervated, to monitor the progress of the ablation/denervationin real time, and to address safety concerns during operation.

FIG. 4 is a side elevational view of a catheter apparatus 100 accordingto embodiments of the present invention. As depicted, the catheterapparatus 100 comprises a shaft 10, a loop 20, a holder 30, a slider 35,a butt 50, a handle 70 and a loop control 90.

The shaft 10 has a proximal end 13 coupled to the holder 30 and a distalend 15 removably connected to the distal portion 11 of the catheterapparatus 100. The shaft 10 has a shape of tube, forming a channel thatextends from the proximal end 13 to the distal end 15, and isdimensioned to allow a stylet and/or a wire(s) to pass therethrough. Thedistal portion 11 may form a passage through which the loop 20 travels,as explained in detail below.

In embodiments, the shaft 10 may be made of silicone, polyurethane (PU),Pebax, or a combination of PU and silicone, or some other biocompatiblepolymers and/or metallic materials. The shaft 10 may be sufficientlylarge enough to house an imaging device, such as an endoscope, as wellas components for ablation/denervation. In embodiments, the shaft 10 mayinclude electrical wires/cables that run from the energy sourcegenerator 204 to the electrodes on the loop 20. In embodiments, theshaft 10 may include wires/cables for providing electrical energy to theendoscope and transmitting visual images from the endoscope to thecontrol unit 200. In embodiments, the shaft 10 may be dimensioned toprovide safe and easy treatment of the target tissue with minimalpercutaneous access site on the patient, for example, on the abdominalregion.

In embodiments, the loop 20 may be removably coupled to the distal end15 of the shaft 10 and mechanically connected to the shaft 10.

The holder 30 is connected to the proximal end 13 of the shaft 10. Morespecifically, the holder 30 may have a structure for accepting theproximal end 13 of the shaft 10 therein and be electrically coupled tothe proximal end 13. In embodiments, a slider 35 may be rotatablycoupled to the holder 30 and the operator may rotate the slider 35 toengage (or disengage) the shaft 10 to (or from) the holder 30.

In embodiments, the holder 30 may include the butt 50 and a terminal 51disposed on one side of the butt 50. The terminal 51 may receive varioustypes of energy from the energy source generator 205 via the wire/cable204 and the energy is delivered from the terminal 51 to the loop 20 viasuitable wires/cables running through the shaft 10. In embodiments, theenergy may be, but not limited to, at least one of a radio-frequency(RF) energy, electrical energy, laser energy, ultrasonic energy,high-intensity focused ultrasound (HIFU) energy, cryogenic energy, andthermal energy. Energy may be delivered to the loop 20, simultaneouslyor sequentially, or selectively. For selective delivery, a clinician canselect, via a user interface of the energy source generator 205, such asan RF generator, a specific electrode to be utilized in the denervationprocess, where the electrode is disposed in the loop 20.

The handle 70 may extend from the butt 50. The handle may have a vacantspace (hole) into which the operator may insert his finger(s) to have afirm grip of the holder 30.

A push-button 61 may be disposed on another side of the butt 50 or oneside of the handle 70. The push-button 61 is operated by the operator tocontrol the energy flow to the loop 20.

The loop control 90 may be hinged on the butt 50 or the handle 70. Theloop control 90 may also have a vacant space (hole) in which theoperator's thumb can be inserted. As described below, the operator maycontrol the loop control 90 to coil/uncoil the loop 20.

FIG. 5 illustrates an example of an operation of a catheter according toan embodiment of the present invention. As shown in the FIG. 5, theslider 35 may be rotated up to about 360 degrees about the longitudinalaxis A of the shaft 10. A rotational direction of the slider 35 may bebidirectional or unidirectional. As the slider 35 rotates, as indicatedby the arrows 92, the loop 20 may also rotate around the longitudinalaxis A of the shaft 10, as indicated by the arrows 90. Thus, a rotationof the loop 20 about the longitudinal axis of the shaft 10 may becontrolled by the rotation of the slider 35.

In embodiments, when moved forward/backward (or upward/downward) by theoperator's finger, as indicated by arrows 94, the loop control 90mechanically controls the loop 20, where the loop control 90 may bedesigned to operate in various modes. In one mode, as the loop control90 moves forward (or downward), the loop 20, which is originally rolled,may be unrolled to a straight segment and extend along the longitudinalaxis A of the shaft 10. As the loop control 90 moves backward (orupward), the loop 20 is rolled to its original shape. In this mode, theoperator may bring the loop 20 near the target tissue or renal artery RAand move the loop control 90 backward to curl the loop 20 around thetarget tissue or renal artery RA.

In another mode, the loop 20 may be retracted into the shaft 10. As theloop control 90 is moved forward (or downward), the loop 20 may emergefrom the distal portion 11 and become a straight segment or curl into asemi-circle. As the loop control 90 is moved backward (or upward), theloop 20 may curl around the target tissue or renal artery RA.

FIG. 6A to FIG. 6D show a loop that curls as it emerges from the shaft10 of the catheter apparatus according to embodiments of the presentinvention. As depicted, the loop 20 includes a body 21 and one or moreelectrodes 23 disposed on the body 21. The loop 20 may remain inside theshaft 10 and distal portion 11 (retracted position) when the loopcontrol 90 is in the neutral position. As the operator moves the loopcontrol 90 forward (or downward), the loop emerges from the distalportion 11, forming a curved segment. As depicted in FIG. 6A to 6D, theloop 20 curls as the tip of the loop 20 proceeds from the position 60toward the position 64.

In embodiments, the body 21 may be made of a flexible material. Inembodiments, the body 21 may be made of thermally non-conductive elasticmaterial so that the energy delivered to the electrodes 23 is localizedonly to a portion(s) of the tissue that the electrodes 23 contact. Asthe localized energy is used to denervate the renal nerves RN (shown inFIG. 3), the potential damage caused by the loop 20 to the tissue nearbythe renal nerves RN may be significantly reduced during operation.

In embodiments, the loop 20 may be flexible and deformable to curlaround a renal artery as discussed in conjunction with FIG. 8. The loop20 may be designed for two different operational modes. In the firstmode, the loop 20 may remain flat when the loop 20 is brought intoproximity to the target tissue, such as the circumferential tissue 5 ofthe renal artery. Then, the operator may manipulate the loop control 90to curl the loop 20 around the circumferential tissue 5 and performdenervation. Upon completing the denervation, the operator may releasethe loop control 90 to uncurl loop 20. In the second mode, the loop 20may remain curled when the distal portion 11 is brought into proximityto the target tissue. Then, the operator may manipulate the loop control90 to uncurl the loop 20, position the loop 20 around the target tissue,release the loop control 90 to curl the loop 20 around the renal arteryand perform denervation.

In embodiments, the electrodes 23 may be disposed on the inner side ofthe body 21 so that the electrodes 23 may contact the circumferentialtissue 5 when the loop 20 curls around the circumferential tissue 5. Inembodiments, the electrodes 23 may extend along the longitudinaldirection of the body 21 and be arranged in parallel to each other. Inone embodiment, the body 21 may be formed of dielectric material and theelectrodes 23 may be formed on the inner surface of the body 21. Inembodiments, the body 21 may have a groove or a channel on the innersurface of the body 21 and the electrodes 23 may be formed by fillingelectrically conductive material in the groove or the channel.

In another embodiment, the body 21 may be formed of electricallyconducting material and the entire surface of the body 21 may be coveredwith dielectric material except the location where the electrodes 23 areto be located. In embodiments, a dielectric body may be disposed betweenthe two electrodes 23 to electrically isolate the electrodes 23 fromeach other.

In embodiments, the electrodes 23 may be formed ofelectrically-conductive elastic material so that they can deform alongwith the body 21 as the body 21 is curled/uncurled. In embodiments, theelectrodes 23 may contact the circumferential tissue 5 surrounding theouter surface of the renal artery and generate heat energy whenelectrical energy, such as RF energy, is supplied, where the heat energymay be used to denervate the renal nerve RN.

In FIG. 6A to 6D, only two electrodes 23 are shown. However, it shouldbe apparent to those of ordinary skill in the art that any suitablenumber of electrodes may be used. For instance, if the electrical energyis supplied as unipolar energy, a single electrode may be used. Inanother example, if the electrical energy is supplied as bipolar energy,two or more electrodes may be used.

FIG. 7A to 7D show a loop 400 according to embodiments of the presentinvention. As depicted, the loop 400 is similar to the loop 20, with thedifference that a sensor 425 is mounted to the body 421. In embodiments,the sensor 425 and the electrodes 423 may be disposed on the inner sideof the body 421.

In embodiments, the sensor 425 may be mounted in the body 421 formed ofdielectric material so that the sensor 425 may be electrically insulatedfrom the electrode 423. The electrodes 423 and sensor 425 may move alongthe body 421 when the loop 420 curls/uncurls around the target tissue.

When the electrode(s) 423 and the sensor 425 curl around thecircumferential tissue 5 of the renal artery, in embodiments, theelectrode(s) 423 and the sensor 425 contact the circumferential tissue5. For instance, the electrode(s) 423 may receive electrical energy suchas RF energy and generate heat energy. The sensor 225 may measure theimpedance of the electrodes 423 or the temperature of thecircumferential tissue. The sensor 425 may be connected to the centralcontroller 200 via a wire(s) that run through the catheter apparatus100, where electrical power for the sensor 425 may be also delivered viaa wire(s).

Information of the measured impedance or temperature may be transmittedto the memory 203 of the catheter system 300. In embodiments, theoperator may diagnose the denervation process using the information. Thepower for delivering thermal energy may also be automatically controlledby the energy source generator 205 or the central controller 200 basedon the information. It is noted that other types of sensor may be usedto measure various quantities, where each quantity may indicate thestatus of the denervation process and provide guidance to the physicianduring operation.

FIG. 8 is a schematic diagram of a catheter, illustrating renaldenervation using the catheter according to embodiments of the presentinvention

As shown in FIG. 8, the distal portion 11 of the catheter is advancedinto proximity of the patient's renal artery RA. The operator mayoperate the loop control 90 so that the loop 20 (or 420) including aplurality of electrodes 23 (or 423) may curl around the circumferentialtissue 5 of the renal artery to thereby directly or indirectly contactthe circumferential tissue of the renal artery RA. The electrodes 23 (or423) may be positioned on a circumferential treatment zone along asegment of the renal artery RA. The electrodes 23 (or 423) may include afirst electrode to deliver thermal energy to a first treatment zone ofthe renal artery RA a second electrode to deliver thermal energy to asecond treatment zone of the renal artery RA.

In embodiments, each of the electrodes may deliver thermal energy to adifferent treatment zone, respectively or deliver thermal energy to thesame treatment zone.

In embodiments, the loop 20 (or 420) may be electrically coupled toenergy source generator 205 for delivery of a desired electrical energyto the electrodes (or 423). In embodiments, the electrical energy may bethermal RF energy using Quantum Molecular Resonance (QMR). A frequencyof the RF energy may be higher than or equal to 4 MHz and may destructat least a portion of the circumferential tissue 5 of the renal arteryRA. In embodiments, the temperature range of the electrodes 23 (or 423)during operation ranges from 60 degrees to 70 degrees.

In embodiments, the loop 20 (or 420) may supply electrical energy to thecircumferential tissue 5 of the renal artery RA to cause renaldenervation through the electrode 23 (or 423). The heat energy, which isgenerated by the electrodes 23 (423), may destruct a portion of thecircumferential tissue of the renal artery, where the circumferentialtissue may include at least one of a renal nerve RN, lymphatics andcapillaries. This may be achieved via contact between the loop 20 (or420) and the circumferential tissue 5 of the renal artery RA. Inembodiments, during the denervation, an impedance of the electrode or atemperature of the circumferential tissue may be measured using thesensor 425.

FIG. 9 is a flow chart 900 illustrating exemplary steps that may becarried out to denervate renal nerves according to embodiments of thepresent invention. The process starts at step 902. At step 902, the loop20 (or 420) that is positioned near a target tissue, such ascircumferential tissue 5 of the renal artery RA. In embodiments, theloop (or 420) may include one or more electrode 23 (or 423). Next, atstep 904, the loop 20 (or 420) may be curled around the target tissue.

At step 906, energy may be delivered to the electrode 23, where theelectrode 23 may convert the energy into heat energy. Then, at step 908,at least a portion of the target tissue may be denervated by the heatenergy.

FIG. 10 is a perspective view of a distal end portion of the catheter inFIG. 4 according to embodiments of the present invention. FIG. 10 alsoincludes a cross sectional view of the loop, taken along the line 53-53,according to embodiments of the present invention.

As depicted, the loop 20 includes a body 21, one or more electrodes 23disposed on a surface of the body 21 and a substrate 25 embedded in thebody 21 and separated from the electrodes 23 by a certain distance.

The body 21 may be made of insulating/elastic materials, such assilicon. The electrodes 23 may extend along the longitudinal directionof the body 21 and may be made of shape-memory alloy, such as Nitinol.The substrate 25 may also extend along the longitudinal direction of thebody 21 like the electrodes 23 and may be made of the same material asthe electrode. The substrate 25 may be electrically insulated from theelectrodes 23. In embodiments, the substrate 25 may be electricallycoupled to the energy source generator 205 via a switch (not shown) andmay receive electrical energy from the energy source generator 205.

If the substrate 25 is not included in the body 21, a portion of theheat energy generated by the electrode 23 may be transferred toward thebackside surface 54 of the body 21, as indicated by the arrows 56. Thesubstrate 25 may prevent the heat energy 56 from being transferred to atissue on the backside surface 54 of the body 21 while most of the heatenergy generated by the electrodes is transferred to the target tissueon the front side surface of the body 21. As a result, the thermalefficiency of the loop 20 may be increased.

The substrate 25 may have a width W1 wider than the width W2 of each ofthe electrodes 23 to more efficiently prevent energy transfer to thetissue that is on the backside surface 54 of the body 21.

In embodiments, the backside surface 54 of the body 21 may be coatedwith a thermally insulating material to block a transfer of the heatenergy 56.

FIG. 11A and FIG. 11B show the loop in FIG. 10 at two differenttemperatures according to embodiments of the present invention.

Referring to FIG. 11A, the loop 20 curls around the circumferentialtissue 5 (e.g., renal artery) as the tip of the loop 20 proceed from theposition 60 toward the position 64 as depicted in FIG. 6A to 6D. Inother words, the operator may mechanically manipulate the loop control90 to curl the loop 20 around the circumferential tissue 5 regardless ofthe temperature of the loop 20. In some cases, the electrodes may firmlycontact the circumferential tissue when the loop curls around thecircumferential tissue by the operator's manipulation. In other cases,the electrodes of the curled loop may not firmly contact thecircumferential tissue for various reasons, such as reduction in themechanical elasticity of the loop due to the mechanical fatiguedeveloped by repeated usage of the loop 20, reduction in the mechanicalforce to tighten the loop and so on.

Referring to FIG. 11B, the electrodes and/or the substrate may be madeof shape-memory alloy whose shape changes at a critical temperature. Inembodiments, as described in conjunction with FIG. 12, the electrodes 23(or substrate 25) made of the shape-memory alloy may be curved at afirst curvature at a low temperature (i.e., below the criticaltemperature) and return to its pre-deformed shape (i.e., curved at asecond curvature) when heated above the critical temperature so that theloop 20 curls tightly around the circumferential tissue 5. For example,the critical temperature may range between 35° C. and 45° C.;preferably, the critical temperature point may be the body temperatureof the patient.

As discussed above, the energy delivered to the electrodes 23 orsubstrate 25 may include one or more of radio-frequency (RF) energy,electrical energy, laser energy, ultrasonic energy, high-intensityfocused ultrasound (HIFU) energy, cryogenic energy, and thermal energy.The critical temperature of the shape-memory alloy that the electrodes23 (or substrate 25) is made of may be reached in two ways. The firstway may be that the critical temperature is reached by the energydelivered to the electrodes 23 and the second way may be that thecritical temperature is reached by the energy delivered to the substrate23. More specifically, in the case of the first way, the energy isdelivered to the electrodes 23, causing the temperature of theelectrodes to rise due to the heat energy generated by the electrodes23. Also, a portion of the heat energy is transferred to the substrate25, causing the temperature of the substrate 25 to rise to the criticaltemperature. As the temperature of the substrate 25 reaches the criticaltemperature, the substrate 25 may curl more tightly around the targettissue as the shape-memory alloy of the substrate 25 may return to thepre-deformed state. The loop 20 including the substrate 25 may curl moretightly around the target tissue so that the electrodes 23 included tothe loop may firmly contact the circumferential tissue, as depicted inFIG. 11B. In the case of the second way, the energy is directlydelivered to the substrate 25 so that the temperature of the substrate25 rises due to the heat energy generated by the substrate. As thetemperature of the substrate 25 reaches the critical temperature, thesubstrate 25 may curl more tightly around the target tissue as theshape-memory alloy of the substrate 25 returns to the pre-deformedstate. The loop 20 including the substrate 25 may curl tightly aroundthe target tissue so that the electrodes 23 included to the loop 20 mayfirmly contact the circumferential tissue, as depicted in FIG. 11B.

As described above, the electrodes 23 may firmly contact thecircumferential tissue by either of the two ways, and as a consequence,the renal denervation may be performed more efficiently.

FIG. 12 shows a deformation of the substrate 25 in FIG. 10 in responseto a temperature change according to embodiments of the presentinvention.

As depicted in FIG. 12, at least a portion of the flat substrate isformed of shape-memory alloy and is deformed to different loopsdepending on its own temperature. In the first mode, when thetemperature (T1) of the substrate 25 is less than the criticaltemperature (Af) (i.e., no energy is delivered to the electrodes 23 orthe substrate 25), a portion of the substrate 25 may be curled bymanipulating the loop control 90. At this time, the first circular loopof the substrate 25 may be formed by a mechanical bending force that maybe applied by the operator's manipulation, where the first diameter (R1)of the first circular loop is large enough to curl around the tissue. Inembodiments, the first circular loop of the substrate 25 may be formedby delivering the energy to the electrodes 23 or the substrate 25 whilethe temperature of the substrate 25 is below the critical temperature.

In the second mode, as shown in FIG. 12, when the temperature (T2) ofthe substrate 25 reaches the critical temperature (Af) by delivering theenergy to the electrodes or the substrate 25, a second circular loop ofthe substrate 25 may be formed, where the second diameter (R2) of thesecond circular loop may be smaller than the first diameter (R1). Theshape-memory alloy of the substrate 25 may be pre-deformed such that thesecond diameter (R2) is slightly larger than the circumferential tissueand the electrodes 23 firmly contact the circumferential tissue in thesecond mode.

In embodiments, the substrate may be made of two-way shape memory alloybut may be made of three-way (or higher order) shape-memory alloy,depending on the application. For instance, the substrate may be made ofthree-way shape-memory alloy and pre-deformed so that the substrate hasreturn to three shapes at three different temperatures.

FIG. 13 illustrate a loop of the catheter in FIG. 4 according to anotherembodiment of the present invention. The loop may be able toautomatically wrap both the tissue and nerves for effective denervationregardless of the nerve distribution. The loop may be available invarious sizes to cover main artery, accessory artery, andearly-branching artery.

According to the present disclosure, it is possible to effectivelyablate e.g., renal nerves while not being as invasive as sympathectomyto treat the resistant hypertension patients. Further, by a procedureusing the catheter, the nerves could safely and completely denervated.

As depicted in FIG. 13, the loop may include a plurality of electrodes1301, a first film 1302, a sensor 1303, a second film 1304 and a thirdfilm 1305.

The first film 1302 may be capable of bending to curl around the tissue.The first film 1302 may be disposed on the second film 1304. The firstfilm 1302 may be made of biocompatible polymers. For example, the firstfilm 1302 may be a polyimide film.

The plurality of electrodes 1301 may be disposed on the first film 1302and arranged in parallel to each other with a predetermined distance.The plurality of electrodes 1301 may contact the circumferential tissuewhen the loop curls around the circumferential tissue.

The plurality of electrodes 1301 may be formed ofelectrically-conductive elastic material so that they can deform alongwith the body as the body is curled/uncurled. By way of example, theplurality of electrodes 1301 may be made of a copper-coated-gold.

Since the plurality of electrodes 1301 are arranged in parallel to eachother, the plurality of electrodes 1301 may form a bipolar configurationlocalizing electrical current path (e.g., thermal energy) between theplurality of electrodes 1301, and the concentration results in heatgeneration at tissue. This configuration confines heat between surfaceof the plurality of electrodes 1301 and an outer wall of the tissue.

The plurality of electrodes 1301 may be configured to curl to directlyor indirectly contact the tissue. The plurality of electrodes 1301 maycontact the circumferential tissue surrounding the outer surface of therenal artery and generate heat energy when electrical energy, such as RFenergy, is supplied, where the heat energy may be used to denervate therenal nerve RN.

In some cases, the plurality of electrodes 1301 may firmly contact thecircumferential tissue when the loop curls around the circumferentialtissue by the operator's manipulation. In other cases, the plurality ofelectrodes 1301 of the curled loop may not firmly contact thecircumferential tissue for various reasons, such as reduction in themechanical elasticity of the loop due to the mechanical fatiguedeveloped by repeated usage of the loop, reduction in the mechanicalforce to tighten the loop and so on.

The plurality of electrodes 1301 may made of the shape-memory alloy maybe curved at a first curvature at a low temperature (i.e., below thecritical temperature) and return to its pre-deformed shape (i.e., curvedat a second curvature) when heated above the critical temperature sothat the loop curls tightly around the circumferential tissue. Forexample, the critical temperature may range between 35° C. and 45° C.;preferably, the critical temperature point may be the body temperatureof the patient.

The critical temperature of the shape-memory alloy that the plurality ofelectrodes 1301 may be made of may be reached in two ways. The criticaltemperature is reached by the energy delivered to the plurality ofelectrodes 1301. More specifically, the energy is delivered to theplurality of electrodes 1301, causing the temperature of the electrodesto rise due to the heat energy generated by the plurality of electrodes1301. Also, a portion of the heat energy is transferred to the entireloop, causing the temperature of the loop to rise to the criticaltemperature. As the temperature of the loop reaches the criticaltemperature, the loop may curl more tightly around the target tissue asthe shape-memory alloy of the plurality of electrodes 1301 may return tothe pre-deformed state. Thus, the loop may curl more tightly around thetarget tissue so that the plurality of electrodes 1301 included to theloop may firmly contact the circumferential tissue.

In the first mode, when the temperature (T1) of the loop is less thanthe critical temperature (Af) (i.e., no energy is delivered to theplurality of electrodes 1301), a portion of the loop may be curled bymanipulating the loop control. At this time, the first circular loop ofthe loop may be formed by a mechanical bending force that may be appliedby the operator's manipulation, where the first diameter (R1) of thefirst circular loop is large enough to curl around the tissue. Inembodiments, the first circular loop of the loop may be formed bydelivering the energy to the plurality of electrodes 1301 while thetemperature of loop is below the critical temperature.

In the second mode, when the temperature (T2) of the loop reaches thecritical temperature (Af) by delivering the energy to the electrodes orthe plurality of electrodes 1301, a second circular loop of loop may beformed, where the second diameter (R2) of the second circular loop maybe smaller than the first diameter (R1). The shape-memory alloy of theplurality of electrodes 1301 may be pre-deformed such that the seconddiameter (R2) is slightly larger than the circumferential tissue and theplurality of electrodes 1301 firmly contact the circumferential tissuein the second mode.

Meanwhile, increasing an energy to reach beyond 2 mm would causeirreversible intima injury resulting in serious complications such asatherosclerosis, thrombosis, or stenosis.

To solve the problem, the plurality of electrodes 1301 may localize heatdistribution between the plurality of electrodes 1301 and the outer wallof the tissue. Therefore, since thermal damage to tunica intima isprevented by concentrating the heat between the plurality of electrodes1301 and the outer wall of the tissue, it is possible to achieve thenerve denervation without injuring the tissue and its adjacent organs.Further, it is possible to maximize nerve denervation by localizing theheat distribution within the nerves and thus neural density can bedecreased enough.

For example, a temperature of the loop may remain 60° C. to form athermal lesion boundary between tunica media and adventitia or thetemperature of the loop may remain 65° C. to extend the lesion boundaryto the tunica media.

The plurality of electrodes 1301 may be configured to supply bipolarenergy. The energy supplied by the plurality of electrodes 1301 may beat least one selected from the group consisting of radio-frequency (RF)energy, electrical energy, laser energy, ultrasonic energy,high-intensity focused ultrasound (HIFU) energy, cryogenic energy,thermal energy

The plurality of electrodes 1301 may include a first electrode todeliver thermal energy to a first treatment zone of the tissue and asecond electrode to deliver thermal energy to a second treatment zone ofthe tissue. Thermal energy delivered to the plurality of electrodes 1301is localized between the first treatment zone and the second treatmentzone.

The sensor 1303 may be disposed on the second film 1304. The sensor 1303may be disposed at a position corresponding to a position between theplurality of electrodes 1301. The sensor 1303 may be electricallyinsulated from the plurality of electrodes 1301. The sensor 1303 maysense at least one of an impedance of the plurality of electrodes 1301and a temperature of the tissue.

The second film 1304 may be disposed on the third film 1305. The secondfilm 1304 may be made of biocompatible metals. By way of example, thesecond film 1304 may be a biocompatible heat-treated stainless steelplate that changes shape from straight to round when emerged from thedistal portion, and it maintains its round shape without external load.The second film 1304 may be coated with a flexible printed circuitboard.

The third film 1305 may also be made of biocompatible polymers. Forexample, the third film 1305 may be a polyimide film.

To achieve complete denervation while preventing damage to the outerwall of the tissue, the applicant analyzed temperature distributionduring denervation with thermoelectrical finite element modeling (FEM)using ANSYS Fluent.

The Bio-heat equation is the governing equation to obtain the thermaldistribution in the tissue. The equation below describes the coupledelectric and thermal problems.

${\rho \; c\frac{\partial T}{\partial t}} = {{{\nabla{\cdot k}}{\nabla T}} + q - Q_{cooling} + Q_{meta}}$

Where T is temperature, t is time, and other parameters are thermalproperties: thermal conductivity of tissue k, the specific heat oftissue c, and mass density of tissue ρ; electrical properties: heatsource from electrical energy q; and temperature cooling effect causedby blood or airflow Q_(cooling). In this simulation, the metabolic heatQ_(meta) is ignored since it is negligible compared to others.

With respect to the electric problem, the 1 MHz wavelength of the signalused in this simulation is more than the size of the plurality ofelectrodes 1301 wrapping the renal artery and nerves. Therefore aquasi-static approximation was applied to solve the electric fields inthe renal artery and nerves. A governing equation used to solveelectrical potential in the tissue is given by:

∇·σ∇V=0

Where σ is the electrical conductivity of the tissue, and V iselectrical potential. The electric field is the gradient of electricalpotential.

E=−∇V

The heat source term q was calculated using Ohm's law.

q=J·E=σ(∇V)²

The electrical conductivity of the tissue is temperature-dependent andis as given by:

σ(T)=σ₀(1+kΔT)

Where σ is electrical conductivity, σ₀ is reference electricalconductivity at 25° C., k is the temperature constant, and ΔT is thetemperature difference from 25° C. We set the temperature constant at2%° C.-1.

A convection effect was applied at the outer arterial wall as a boundarycondition:

Q _(air) =h(T−T ₀)

Here, free convection at walls exposed to CO₂ gas with convective heattransfer coefficient (h) of 25 Wm-2K-1 and free stream temperature (T₀)of 300 K are assumed.

In renal denervation, due to the detachment of target renal artery fromfat, periarterial connective tissue and capillaries, the blood perfusionin the artery will be decreased. In addition, the cooling effect by bulkblood flow in this detached artery is more dominant than bloodperfusion. Therefore, fluid flow is used to simulate blood coolingeffect and not blood perfusion in the lumen of the artery. Blood coolingeffect (Qblood) was simulated using a velocity inlet (blood flow rate)and a static pressure outlet as 0 Pa. In ANSYS Fluent, the Bio-heatequation was coded and applied to model via a built-in user-definedfunction. Using the user-defined scalar and the specified value at bothelectrodes, with zero specified flux at the other parts, the transientsituation with 1 second time step size and 90-time steps in in vitrostimulation and the steady-state situation in vivo simulation issimulated.

After establishing a validity of using a meshing method, bio-heatequation, and setting boundary conditions in vitro, the applicantextended these techniques to in-vivo simulation with the renal arterymodel. In in-vivo simulation, the artery 3D was designed based onprevious histological studies where the diameter of the artery, thediameter of the lumen, and thickness of the artery wall were 5 mm, 2 mm,and 1.5 mm, respectively. The arterial wall was composed of tunica mediaand adventitia. To analyze the heat distribution in various in-vivosimulations, the ratio of the thickness of the tunica media andadventitia was changed while maintaining the total diameter of theartery as 5 mm. Compared to a phantom gel in in-vitro modeling, in invivo arterial blood flow was taken into account with the flow rates from0.28 to 0.68 m/s. The blood temperature was set as 310 K with otherconditions remaining the same. At electrode-tissue interfaces, theelectric potential of an electrode was zero. The electric potential ofthe other electrode was chosen to make the temperature between the twoelectrodes at 60 or 65° C. in the steady-state condition. The modelingdomain was a cuboid with 30 mm (height)×20 mm (length)×20 mm (width) inthe phantom simulation. The artery was of the cylinder in shape with aheight of 20 mm and a radius of 2.5 mm in vivo simulation. The defaultelement size was 0.1 mm, and the element size near the electrodes was0.05 mm.

Here, the phantom was manufactured by mixing 6 L water with 48 g gellingagent (polyacrylic acid solution, Sigma-Aldrich) in a 160 mm×430 mm×170mm acrylic water tank. In this phantom gel, we considered that theconvection effect was almost zero, mass density and specific heat werethe same with water. The electrical conductivity of the phantom wasmeasured using an impedance analyzer (E4990A, Keysight Technologies).

FIGS. 14A and 14B show the heat distribution at x=0 and x=3 planes inthe FEM model of the parameter-controlling phantom gel after heating 90seconds. The simulated peak temperature distribution in x=3 plane ishigher than the temperature in x=0 plane. The results confirm that thecatheter apparatus could focus heat inside the loop and between parallelelectrodes. This simulation model was validated by comparing thesimulated temperature profiles with experimental results at a total of169 points (13 points for each 13 section planes). The temperature atthe center of the loop is measured at 14 points, 13 points are for fiberoptic temperature probe, and the final point is for the sensor e.g.,thermocouple probes integrated within the loop. The simulation andexperimental results of normalized temperatures measured by the sensorin simulation and experiment are shown in FIG. 14C using scatter plots.The coefficient of determination in the scatter is 0.859, and theoverall average error is 6.97%. The effect of the thermal conductivityfrom the sensitivity analyses shows that the peak temperature did notdiffer more than 1.2° C. between simulations and experimental methods,which is an acceptable difference. This good agreement between thesimulation study and validation experiments confirmed the credibility ofthe simulation method and modeling.

The applicant further utilized a numerical simulation model to evaluatethe thermal distribution at the loop of the artery 3D model. The model'sartery length, lumen diameter, the thickness of tunica media, andadventitia were set to 20 mm, 2 mm, 0.6 mm, and 0.9 mm respectively,with the blood flow rate set to 0.68 m/s. With the temperature of theloop maintained at 65° C., the peak temperature distribution at thecross-section and the longitudinal section of the 3D artery model areshown in FIGS. 15A and 15B.

In the numerical simulation model, the heat is concentrated on theoutside of the artery, in the cross-section, and between the parallelelectrodes in the longitudinal section. The temperature profiles at thecenter of two parallel electrodes are shown in FIG. 16.

As an isothermal line, which is the thermal lesion boundary, or anonviable volume, 50° C. was set. Typically the renal nerves aredistributed in tunica adventitia and periarterial connective tissue.Therefore, the ideal thermal lesion boundary should be located in theborder between tunica media and adventitia while preventing thermaldamage to tunica intima or lumen.

FIG. 16 shows the border as a dashed line at x=1.6 mm. When thetemperature of the loop (hereafter, loop temperature) remained at 60° C.1601, the thermal lesion boundary was formed between tunica media andadventitia. As the temperature of the loop reached 65° C. 1603 to 70° C.1605, the lesion boundary extended to the tunica media.

In addition, the applicant further evaluated thermal distribution witharteries of different sizes when ablating at loop temperature between60° C. and 65° C., as shown in FIGS. 17A to 17E. Here, FIG. 17A shows aheat distribution in an artery with a lumen diameter 1701 of 2 mm,tunica media thickness 1702 of 0.5 mm and tunica adventitia thickness1703 of 1 mm. FIG. 17B shows a heat distribution in an artery with alumen diameter 1704 of 2 mm, tunica media thickness 1705 of 0.6 mm andtunica adventitia thickness 1706 of 0.9 mm. FIG. 17C shows a heatdistribution in an artery with a lumen diameter 1707 of 2 mm, tunicamedia thickness 1708 of 0.7 mm and tunica adventitia thickness 1709 of0.8 mm. FIG. 17D shows a heat distribution in an artery with a lumendiameter 1710 of 1.4 mm, tunica media thickness 1711 of 0.6 mm andtunica adventitia thickness 1712 of 1.2 mm. FIG. 17E shows a heatdistribution in an artery with a lumen diameter 1713 of 2.6 mm, tunicamedia thickness 1714 of 0.6 mm and tunica adventitia thickness 1715 of0.6 mm. In FIGS. 17A to 17F, a dashed line indicates the isothermal lineof 50° C.

Referring to FIGS. 17A to 17C, with the diameter of lumen fixed at 2 mm,the thermal lesion boundaries were at 1.3 mm to 1.5 mm from the centerof the artery for various of tunica media thickness, e.g., 0.5 mm, 0.6mm, and 0.7 mm. Referring to FIGS. 17D and 17E, when the thickness oftunica media was fixed, and the diameter of the lumen was set at 1.4 mmand 2.6 mm, the thermal lesion boundaries were 1.1 mm to 1.3 mm and 1.6mm, respectively, from the center of the artery.

Further, the applicant evaluated thermal distribution with an arterywhen ablating at loop temperature between 65° C. and 70° C. as shown inFIG. 17F. At this time, lumen diameter 1716, tunica media thickness1717, and tunica adventitia thickness 1718 were set to 2 mm, 0.6 mm and0.9 mm respectively.

The electric potentials of an electrode in the simulation of FIGS. 17Ato 17E were 20, 20.2, 20.3, 17.3, and 24.3 V. When the blood flow ratein the artery was varied, 0.28, 0.48 and 0.68 m/s, the thermal lesionboundaries were about 1.39 mm from the center of the artery, and theelectrode electric potentials were 19.7, 19.9, and 20.2 V, respectively.These results show that the ablation with loop temperature generated thesame heat distribution even when the blood flow rates were varied.Finally, from the simulation, the applicant derived that the looptemperature should be 60° C. to 65° C. to completely ablate nerves whileminimizing the damage on tunica intima.

In embodiments, the duration of treatment is determined based oncumulative equivalent minutes at 43° C. (CEM 43), which is a thermaldose unit used for determining damage threshold for a specific tissue.The CEM 43 is a simple concept that translates all differenttemperature-time histories to a single number representing a “thermalisoeffect dose”. The CEM 43 is calculated using the equation (10):

${{{CEM}\mspace{14mu} 43} = {\sum\limits_{t = 0}^{t = {FINAL}}{R^{({43 - T})}t}}},{R = \{ \begin{matrix}{{{0.2}5},{T < {43{^\circ}\mspace{14mu} {C.}}}} \\{{0{.5}},{T \geq {43{^\circ}\mspace{14mu} {C.}}}}\end{matrix} }$

Where t is time (min), T is the temperature (° C.) at time t, and R is aconstant value.

In embodiments, the loop temperature may be between 48° C. and 65° C.with an ablation duration of between 70 s and 150 s for safe andeffective renal denervation.

For example, if temperature T is maintained at 50° C. during treatment,the treatment duration may be between 70 s and 120 s after consideringthe threshold as CEM 43 of the renal artery, where the thermal dose atnerves must be more than the threshold needed to ablate the nerve.According to this process, the loop temperature may be between 60° C.and 65° C. with an ablation duration of between 70 s and 120 s for safeand effective renal denervation.

For example, if temperature T is maintained at 50° C. during treatment,the treatment duration may be between 120 s and 150 s after consideringthe threshold as CEM 43 of the renal artery, where the thermal dose atnerves must be more than the threshold needed to ablate the nerve.According to this process, the loop temperature may be between 48° C.and 50° C. with an ablation duration of between 120 s and 150 s for safeand effective renal denervation.

The apparatus described herein can be used to treat not onlyhypertension, but also other suitable types of diseases, such as chronicrenal diseases, cardiovascular disorders, cardiac arrhythmias, andclinical syndromes where the renal afferent activation is involved.Using the catheter in embodiments, as compared to percutaneous catheterand surgical instrumentation, the physician may treat the diseases in aneasier and safer manner.

In the description, numerous details are set forth for purposes ofexplanation in order to provide a thorough understanding of the presentinvention. However, it will be apparent to one skilled in the art thatnot all of these specific details are required in order to practice thepresent invention.

Additionally, while specific embodiments have been illustrated anddescribed in this specification, those of ordinary skill in the artappreciate that any arrangement that is calculated to achieve the samepurpose may be substituted for the specific embodiments disclosed. Thisdisclosure is intended to cover any and all adaptations or variations ofthe present invention, and it is to be understood that the terms used inthe following claims should not be construed to limit the invention tothe specific embodiments disclosed in the specification. Rather, thescope of the invention is to be determined entirely by the followingclaims, which are to be construed in accordance with the establisheddoctrines of claim interpretation, along with the full range ofequivalents to which such claims are entitled.

What is claimed is:
 1. A catheter apparatus for perivascular nervedenervation, comprising: a shaft having a distal end; and a loopdisposed near the distal end and configured to curl around a tissue andreceive, via the shaft, energy for nerve denervation at least a portionof the tissue, wherein the loop includes: a body capable of bending tocurl around the tissue; an electrode disposed on the body; and asubstrate embedded in the body and separated from the electrode, and thenerve denervation is performed at a loop temperature of 48° C. to 65° C.for 70 to 150 seconds.
 2. The catheter apparatus of claim 1, wherein thenerve denervation is performed at the loop temperature of 48° C. to 50°C. for 120 to 150 seconds.
 3. The catheter apparatus of claim 1, whereinthe nerve denervation is performed at the loop temperature of 60° C. to65° C. for 70 to 120 seconds.
 4. The catheter apparatus of claim 3,wherein the tissue is an artery including a lumen, a tunica media and atunica adventitia.
 5. The catheter apparatus of claim 4, wherein athermal lesion boundary between the tunica media and the tunicaadventitia is 1.3 mm to 1.5 mm.
 6. The catheter apparatus of claim 5,wherein the lumen has a diameter of 2 mm, a tunica media has a thicknessof 0.5 mm and a tunica adventitia has a thickness of 1 mm.
 7. Thecatheter apparatus of claim 4, wherein a thermal lesion boundary betweenthe tunica media and the tunica adventitia is 1.1 mm to 1.3 mm.
 8. Thecatheter apparatus of claim 7, wherein the lumen has a diameter of 1.4mm, a tunica media has a thickness of 0.6 mm and a tunica adventitia hasa thickness of 1.2 mm.
 9. A catheter apparatus for perivascular nervedenervation, comprising: a shaft having a distal end; and a loopdisposed near the distal end and configured to curl around a tissue andreceive, via the shaft, energy to denervate at least a portion of thetissue, wherein the loop includes: a first film capable of bending tocurl around the tissue; a plurality of electrodes disposed on the firstfilm and arranged in parallel to each other with a predetermineddistance; and a sensor disposed at a position corresponding to aposition between the plurality of electrodes, and the nerve denervationis performed at a loop temperature of 48° C. to 65° C. for 70 to 150seconds.
 10. The catheter apparatus of claim 9, wherein the nervedenervation is performed at the loop temperature of 48° C. to 50° C. for120 to 150 seconds.
 11. The catheter apparatus of claim 9, wherein thenerve denervation is performed at the loop temperature of 60° C. to 65°C. for 70 to 120 seconds.
 12. The catheter apparatus of claim 11,wherein the tissue is an artery including a lumen, a tunica media and atunica adventitia.
 13. The catheter apparatus of claim 12, wherein athermal lesion boundary between the tunica media and the tunicaadventitia is 1.3 mm to 1.5 mm.
 14. The catheter apparatus of claim 13,wherein the lumen has a diameter of 2 mm, a tunica media has a thicknessof 0.5 mm and a tunica adventitia has a thickness of 1 mm.
 15. Thecatheter apparatus of claim 12, wherein a thermal lesion boundarybetween the tunica media and the tunica adventitia is 1.1 mm to 1.3 mm.16. The catheter apparatus of claim 15, wherein the lumen has a diameterof 1.4 mm, a tunica media has a thickness of 0.6 mm and a tunicaadventitia has a thickness of 1.2 mm.
 17. A method for perivascularnerve denervation using a catheter having a loop, comprising:positioning the loop near a tissue, the loop including an electrode anda substrate; delivering energy to at least one of the electrode and thesubstrate, thereby to cause the loop to curl around the tissue; causingthe at least one of the electrode and the substrate to convert theenergy into heat energy; and denervating at least a portion of thetissue using the heat energy at a loop temperature of 48° C. to 65° C.for 70 to 150 seconds.
 18. The method of claim 17, wherein thedenervating includes denervating at least a portion of the tissue usingthe heat energy at a loop temperature of 48° C. to 50° C. for 120 to 150seconds.